{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T13:17:17Z","timestamp":1793798237973,"version":"4.6.1"},"reference-count":42,"publisher":"American Medical Association (AMA)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"\n Importance<\/jats:title>\n Energy homeostatic dysregulation may constitute 1 module of the heterogeneous pathophysiology of major depressive disorder (MDD), potentially manifesting as a distinctive symptom profile.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To test whether the shared genetic liability of metabolic, interoceptive, and motivational pathways involved in energy homeostasis regulation is associated with the expression of specific MDD symptoms.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This study used summary-level data from large genome-wide association studies and individual-level data from 2 prospective psychiatric cohorts, the CoLaus|PsyCoLaus (population-based) and Netherlands Study of Depression and Anxiety (NESDA; clinically enriched) cohorts. Data were retrieved and analyzed from May 2023 through November 2024. A lifetime diagnosis of MDD was ascertained with semistructured diagnostic interviews. The sample comprised 1407 MDD cases and 2020 controls from CoLaus|PsyCoLaus and 1803 MDD cases and 266 controls from NESDA.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n Genomic structural equation modeling was applied to model a unique underlying factor capturing the common genetic liability shared among metabolic and interoceptive signals (body mass index, triglycerides, fasting glucose, C-reactive protein, leptin) and motivational (anhedonia) processes. From this underlying factor, a polygenic score (PGS) was derived, indexing the shared genetic liability of traits potentially involved in energy homeostasis regulation.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n A total of 15 depressive symptoms endorsed by participants during MDD.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 1407 MDD cases (66.2% female; median year of birth [YOB], 1956) and 2020 controls (44.3% female; median YOB, 1955) from CoLaus|PsyCoLaus and 1803 MDD cases (68.3% female; median YOB, 1962) and 266 controls (56.0% female; median YOB, 1960) from NESDA, multiple significant bidirectional mendelian randomization estimates and genetic correlations (\n r<\/jats:italic>\n \u2009=\u20090.11-0.81) indicated a shared genetic basis between the selected traits, which was modeled as a latent homeostatic factor with genomic structural equation modeling. In cohort data, the PGS indexing the latent homeostatic factor was significantly (false discovery rate, &amp;lt;5%) higher in MDD cases endorsing appetite increase and hypersomnia when contrasted with both controls (appetite increase odds ratio [OR], 2.25 [95% CI, 2.00-2.53];\n P<\/jats:italic>\n \u2009=\u20099.03\u2009\u00d7\u200910\n \u221241<\/jats:sup>\n ; hypersomnia OR, 1.22 [95% CI, 1.10-1.35];\n P<\/jats:italic>\n \u2009=\u20091.15\u2009\u00d7\u200910\n \u221204<\/jats:sup>\n ) and other MDD cases (appetite increase OR, 1.88 [95% CI, 1.63-2.18];\n P<\/jats:italic>\n \u2009=\u20092.38\u2009\u00d7\u200910\n \u221217<\/jats:sup>\n ; hypersomnia OR, 1.18 [95% CI, 1.05-1.33];\n P<\/jats:italic>\n \u2009=\u20095.80\u2009\u00d7\u200910\n \u221203<\/jats:sup>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n This study identified a module of depression pathophysiology characterized by altered energy homeostasis and associated with the expression of specific symptoms reflecting energy saving and intake responses. These findings could be used to identify patients with depression at higher metabolic risk and could pave the way for the development of targeted treatments.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2025.1858","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T15:00:43Z","timestamp":1754492443000},"page":"992","source":"Crossref","is-referenced-by-count":15,"title":["The Role of Energy Homeostasis in Depression Pathophysiology and Its Heterogeneity"],"prefix":"10.1001","volume":"82","author":[{"given":"Giorgio","family":"Pistis","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Pierre F.","family":"Strippoli","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens H.","family":"van Dalfsen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Vaucher","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Specialties, Service of Internal Medicine, Fribourg Hospital and University of Fribourg, Fribourg, Switzerland"},{"name":"Department of Medicine, Service of Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Kutalik","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, University of Lausanne, Lausanne, Switzerland"},{"name":"Swiss Institute of Bioinformatics, Lausanne, Switzerland"},{"name":"University Center for Primary Care and Public Health, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Vollenweider","sequence":"additional","affiliation":[{"name":"Department of Medicine, Service of Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda W. H. J.","family":"Penninx","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands"},{"name":"Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands"},{"name":"Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Stress & Sleep Program, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Preisig","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Milaneschi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands"},{"name":"Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands"},{"name":"Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Stress & Sleep Program, Amsterdam, the Netherlands"},{"name":"Amsterdam Neuroscience, Complex Trait Genetics Program, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"1","key":"yoi250036r1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/s41572-023-00454-1","article-title":"Major depressive disorder.","volume":"9","author":"Marx","year":"2023","journal-title":"Nat Rev Dis Primers"},{"issue":"11","key":"yoi250036r2","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1001\/jamapsychiatry.2024.2047","article-title":"Unveiling the structure in mental disorder presentations.","volume":"81","author":"Spiller","year":"2024","journal-title":"JAMA Psychiatry"},{"issue":"10","key":"yoi250036r3","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1038\/s43587-024-00716-x","article-title":"The brain-body energy conservation model of aging.","volume":"4","author":"Shaulson","year":"2024","journal-title":"Nat Aging"},{"issue":"6669","key":"yoi250036r4","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1126\/science.adh8285","article-title":"Sleep and the hypothalamus.","volume":"382","author":"Adamantidis","year":"2023","journal-title":"Science"},{"issue":"6665","key":"yoi250036r5","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl7398","article-title":"Integrative neurocircuits that control metabolism and food intake.","volume":"381","author":"Br\u00fcning","year":"2023","journal-title":"Science"},{"issue":"7874","key":"yoi250036r6","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s41586-021-03811-w","article-title":"A metabolic function of the hippocampal sharp wave-ripple.","volume":"597","author":"Tingley","year":"2021","journal-title":"Nature"},{"issue":"5","key":"yoi250036r7","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/j.biopsych.2022.11.003","article-title":"Inflammation-related functional and structural dysconnectivity as a pathway to psychopathology.","volume":"93","author":"Goldsmith","year":"2023","journal-title":"Biol Psychiatry"},{"issue":"10","key":"yoi250036r8","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1001\/jamapsychiatry.2022.2464","article-title":"Functional connectivity of the nucleus accumbens and changes in appetite in patients with depression.","volume":"79","author":"Kroemer","year":"2022","journal-title":"JAMA Psychiatry"},{"key":"yoi250036r9","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2024.101166","article-title":"Immuno-metabolic depression: from concept to implementation.","volume":"48","author":"Penninx","year":"2024","journal-title":"Lancet Reg Health Eur"},{"issue":"1","key":"yoi250036r10","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.cell.2015.03.008","article-title":"The hunger genes: pathways to obesity.","volume":"161","author":"van der Klaauw","year":"2015","journal-title":"Cell"},{"issue":"8031","key":"yoi250036r11","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1038\/s41586-024-07922-y","article-title":"Pathogenic hypothalamic extracellular matrix promotes metabolic disease.","volume":"633","author":"Beddows","year":"2024","journal-title":"Nature"},{"issue":"8","key":"yoi250036r12","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1001\/jamapsychiatry.2014.411","article-title":"Depression with atypical features and increase in obesity, body mass index, waist circumference, and fat mass: a prospective, population-based study.","volume":"71","author":"Lasserre","year":"2014","journal-title":"JAMA Psychiatry"},{"issue":"12","key":"yoi250036r13","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1001\/jamapsychiatry.2017.3016","article-title":"Genetic association of major depression with atypical features and obesity-related immunometabolic dysregulations.","volume":"74","author":"Milaneschi","year":"2017","journal-title":"JAMA Psychiatry"},{"issue":"5","key":"yoi250036r14","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.biopsych.2020.01.014","article-title":"Depression heterogeneity and its biological underpinnings: toward immunometabolic depression.","volume":"88","author":"Milaneschi","year":"2020","journal-title":"Biol Psychiatry"},{"issue":"1","key":"yoi250036r15","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/s41398-019-0635-y","article-title":"Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure.","volume":"9","author":"Ward","year":"2019","journal-title":"Transl Psychiatry"},{"issue":"1","key":"yoi250036r16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"\u2018Mendelian randomization\u2019: can genetic epidemiology contribute to understanding environmental determinants of disease?","volume":"32","author":"Smith","year":"2003","journal-title":"Int J Epidemiol"},{"issue":"5","key":"yoi250036r17","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/s41562-019-0566-x","article-title":"Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits.","volume":"3","author":"Grotzinger","year":"2019","journal-title":"Nat Hum Behav"},{"issue":"7","key":"yoi250036r18","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data.","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet Epidemiol"},{"issue":"4","key":"yoi250036r19","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator.","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet Epidemiol"},{"issue":"2","key":"yoi250036r20","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.","volume":"44","author":"Bowden","year":"2015","journal-title":"Int J Epidemiol"},{"issue":"11","key":"yoi250036r21","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.1002\/sim.7221","article-title":"A framework for the investigation of pleiotropy in two-sample summary data mendelian randomization.","volume":"36","author":"Bowden","year":"2017","journal-title":"Stat Med"},{"issue":"5","key":"yoi250036r22","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from mendelian randomization between complex traits and diseases.","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"issue":"1","key":"yoi250036r23","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA.","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat Commun"},{"issue":"1","key":"yoi250036r24","doi-asserted-by":"publisher","first-page":"3222","DOI":"10.1038\/s41467-019-11181-1","article-title":"Genetic mapping of cell type specificity for complex traits.","volume":"10","author":"Watanabe","year":"2019","journal-title":"Nat Commun"},{"key":"yoi250036r26","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/1471-244X-9-9","article-title":"The PsyCoLaus study: methodology and characteristics of the sample of a population-based survey on psychiatric disorders and their association with genetic and cardiovascular risk factors.","volume":"9","author":"Preisig","year":"2009","journal-title":"BMC Psychiatry"},{"key":"yoi250036r27","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1471-2261-8-6","article-title":"The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome.","volume":"8","author":"Firmann","year":"2008","journal-title":"BMC Cardiovasc Disord"},{"key":"yoi250036r28","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.jad.2021.03.026","article-title":"Cohort profile of the longitudinal Netherlands Study of Depression and Anxiety (NESDA) on etiology, course and consequences of depressive and anxiety disorders.","volume":"287","author":"Penninx","year":"2021","journal-title":"J Affect Disord"},{"issue":"11","key":"yoi250036r29","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1001\/archpsyc.1994.03950110009002","article-title":"Diagnostic interview for genetic studies\u2014rationale, unique features, and training.","volume":"51","author":"Nurnberger","year":"1994","journal-title":"Arch Gen Psychiatry"},{"issue":"1","key":"yoi250036r30","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/0022-3956(94)90036-1","article-title":"Reliability and validity studies of the WHO\u2013Composite International Diagnostic Interview (CIDI): a critical review.","volume":"28","author":"Wittchen","year":"1994","journal-title":"J Psychiatr Res"},{"issue":"1","key":"yoi250036r31","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1038\/s41467-019-09718-5","article-title":"Polygenic prediction via bayesian regression and continuous shrinkage priors.","volume":"10","author":"Ge","year":"2019","journal-title":"Nat Commun"},{"issue":"4","key":"yoi250036r32","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1136\/ebmental-2019-300117","article-title":"How to perform a meta-analysis with R: a practical tutorial.","volume":"22","author":"Balduzzi","year":"2019","journal-title":"Evid Based Ment Health"},{"issue":"7","key":"yoi250036r33","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giz082","article-title":"PRSice-2: polygenic risk score software for biobank-scale data.","volume":"8","author":"Choi","year":"2019","journal-title":"Gigascience"},{"issue":"1","key":"yoi250036r34","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/s41398-021-01236-7","article-title":"Obesity and atypical depression symptoms: findings from mendelian randomization in two European cohorts.","volume":"11","author":"Pistis","year":"2021","journal-title":"Transl Psychiatry"},{"issue":"4","key":"yoi250036r35","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1017\/S0033291720002342","article-title":"Depression with atypical neurovegetative symptoms shares genetic predisposition with immuno-metabolic traits and alcohol consumption.","volume":"52","author":"Badini","year":"2022","journal-title":"Psychol Med"},{"issue":"3","key":"yoi250036r36","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/S0165-1781(02)00241-X","article-title":"Psychomotor changes in melancholic and atypical depression: unipolar and bipolar-II subtypes.","volume":"112","author":"Benazzi","year":"2002","journal-title":"Psychiatry Res"},{"issue":"6","key":"yoi250036r37","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/s44161-024-00488-y","article-title":"Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease.","volume":"3","author":"Bergstedt","year":"2024","journal-title":"Nat Cardiovasc Res"},{"issue":"12","key":"yoi250036r38","doi-asserted-by":"publisher","first-page":"7393","DOI":"10.1038\/s41380-021-01188-w","article-title":"Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts.","volume":"26","author":"Milaneschi","year":"2021","journal-title":"Mol Psychiatry"},{"issue":"4","key":"yoi250036r39","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/nm1372","article-title":"Induction of leptin resistance through direct interaction of C-reactive protein with leptin.","volume":"12","author":"Chen","year":"2006","journal-title":"Nat Med"},{"key":"yoi250036r40","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.bbi.2019.10.006","article-title":"Appetite change profiles in depression exhibit differential relationships between systemic inflammation and activity in reward and interoceptive neurocircuitry.","volume":"83","author":"Cosgrove","year":"2020","journal-title":"Brain Behav Immun"},{"issue":"4","key":"yoi250036r41","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/s41588-020-0594-5","article-title":"Minimal phenotyping yields genome-wide association signals of low specificity for major depression.","volume":"52","author":"Cai","year":"2020","journal-title":"Nat Genet"},{"issue":"3","key":"yoi250036r42","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1001\/jamapsychiatry.2020.4373","article-title":"Dissecting depression biological and clinical heterogeneity\u2014the importance of symptom assessment resolution.","volume":"78","author":"Milaneschi","year":"2021","journal-title":"JAMA Psychiatry"},{"key":"yoi250036r25","doi-asserted-by":"crossref","unstructured":"Cu\u00e9llar-Partida? G, Lundberg? M, Kho? PF, . Complex-Traits Genetics Virtual Lab: a community-driven web platform for post-GWAS analyses.? bioRxiv. 2019:518027. doi:10.1101\/518027","DOI":"10.1101\/518027"}],"container-title":["JAMA Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamapsychiatry\/articlepdf\/2836882\/jamapsychiatry_pistis_2025_oi_250036_1759153291.18035.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T15:00:39Z","timestamp":1759330839000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamapsychiatry\/fullarticle\/2836882"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,1]]},"references-count":42,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamapsychiatry.2025.1858","relation":{},"ISSN":["2168-622X"],"issn-type":[{"value":"2168-622X","type":"print"}],"subject":[],"published":{"date-parts":[[2025,10,1]]}}}